Obesity is a nutritional disorder in western societies, and is a serious health concern because of its association with diseases and conditions such as adult-onset diabetes, hypertension, and heart disease. Obesity is currently described by the World Health Organization (WHO) as an epidemic in many industrialized nations, and it has recently been reported by the Worldwatch Institute in Washington D.C., that over 1 billion people worldwide are now suffering from the health consequences of over-consumption. In the United States alone, where more than one in three adults are classified as obese, the condition is estimated to cause 300,000 premature deaths each year. The costs associated with obesity and its related illnesses causes a significant debt in the US economy—both from the direct cost of treating conditions triggered by obesity, and from the lost in economic productivity (Wolf, A. M. & Colditz, G. A. Obes. Res. 6, 97-106 (1998)).
Previous studies have shown that cannabinoids and their antagonists may regulate feeding and body weight through activation or inhibition of cannabinoid receptor type 1 (CB1) like Anandamide or Rimonabant (SR141716A) respectively, or by activation of PPAR-α (peroxisome proliferator activate receptor alpha), a key regulator of lipid metabolism and energy balance in mammals. Oleoylethanolamide (OEA) is a naturally occurring lipid amide that reduces food intake, promotes lipolysis and decreases body weight gain in rodents by activating PPAR-α. The biological deactivation of OEA is not fully understood but is likely to involve the enzymatic hydrolysis of this lipid amide to oleic acid and ethanolamine. Two structurally distinct OEA-hydrolyzing enzymes have been characterized: fatty-acid amide hydrolase (FAAH), an intracellular membrane-bound serine hydrolase, and N-acetylethanoamine-hydrolyzing acid amidase, a lysosomal cysteine hydrolase. Giuseppe et al. (J. Pharm. Exper. Therap. 318 (2), pp. 563-570, 2006), describe OEA analogs that resist enzymatic hydrolysis, activate PPAR-α, and reduce feeding when administered to rodents in vivo either parenterally or orally. The most potent of these compounds, (Z)—(R)-9-octadecenamide, N-2(hydroxyethyl,1-methyl) (KDS-5104), is reported to stimulate transcriptional activity of PPAR-α with an EC50 of 100 nm.
Obesity, if left unabated, can have dire health consequences, such as adult-onset diabetes (Type II diabetes), dyslipidemia, hyperinsulinemia, hypertension, heart disease (e.g., coronary heart disease, hear attack, heart failure or heart arrhythmias), thromboembolism, osteoarthritis, gout, varicose veins, increased incidence of stroke, low self esteem, hirsutism, sweating, hypoventilation, sleep apnea, respiratory problems, breathlessness, cancer (including breast cancer, cancer of the colon, cancer of the uterus and cancer of the pancreas), kidney disease, gallstones, gallbladder disease, infertility, problems with pregnancy, menorrhagia, and accelerated morbidity and mortality. Innovative approaches are urgently needed at both the basic science and clinical levels to treat obesity.